This invention relates to a novel granulate and a novel oral solid dosage formulation comprising an active ingredient and one or more carriers. Moreover the invention relates to a wet granulation method for preparing the granulate as well as a wet granulation method for preparing the oral solid dosage form.
High shear mixers are widely used in the pharmaceutical industry for blending and granulation (cf. Handbook of pharmaceutical granulation technology, chapter 7, xe2x80x9cDrugs and the pharmaceutical sciencesxe2x80x9d, vol. 81, 1997). Blending and wet massing is accomplished by high mechanical agitation by an impellar and chopper. High shear mixers have applications other than wet granulation, as it can be used for melt granulation and pelletization. When melt granulation or pelletization is performed, energy for melting the binder is supplied by agitation of the impellar and external heating of the bowl.
Compounds of Formula I 
wherein R is hydrogen or C1-6alkyl; or a pharmaceutically acceptable salt thereof, are described in i.a. U.S. Pat. No. 5,280,040. This patent describes the preparation of these compounds, as well as their use for reducing or preventing bone loss. The preparation of pharmaceutical compositions is also described.
Centchroman, which is 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-pyrrolidin-1-yl)ethoxy)phenyl]-7-methoxychroman, is a non-steroidal compound known to have antiestrogenic activity. It is in use in India as an oral contraceptive (see, for example, Salman et al., U.S. Pat. No. 4,447,622; Singh et al., Acta Endocrinal (Copenh) 126 (1992), 444-450; Grubb, Curr Opin Obstet Gynecol 3 (1991), 491-495; Sankaran et al., Contraception 9 (1974), 279-289; Indian Patent Specification No. 129187). Centchroman has also been investigated as an anti-cancer agent for treatment of advanced breast cancer (Misra et al., Int J Cancer 43 (1989), 781-783. Recently, centchroman as a racemate has been found as a potent cholesterol lowering pharmaceutical agent expressed by a significant decrease of the serum concentrations (S. D. Bain et al., J Min Bon Res 9 (1994), S 394).
Levormeloxifene, (xe2x88x92)-3R,4R -trans-7-methoxy-2,2-dimethyl-3-phenyl4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane, is a particular preferred compound from this series of 3,4-diarylchromans. Levormeloxifene may be used in human and veterinary medicine for the regulation of bone metabolism. It may be used, for example, in the treatment of patients suffering from bone loss due to osteoporosis (including post-menopausal osteoporosis and glucocorticoid-related osteoporosis), Paget""s disease, hyperparathyroidism, hypercalcemia of malignancy and other conditions characterized by excessive rates of bone resorption and/or decreased rates of bone formation.
The 3,4-diarylchromans are prepared according to known methods, such as those disclosed in U.S. Pat. No. 3,340,276 to Carney et al., U.S. Pat. No. 3,822,287 to Bolger, and Ray et al., J Med Chem 19 (1976), 276-279, the contents of which are incorporated herein by reference. Conversion of the cis isomer to the trans configuration by means of an organometallic base-catalyzed rearrangement is disclosed in U.S. Pat. No. 3,822,287. The optically active d- and I-enantiomers may be prepared as disclosed by Salman et al. in U.S. Pat. No. 4,447,622 (incorporated herein by reference) by forming an optically active acid salt which is subjected to alkaline hydrolysis to produce the desired enantiomer. The resolvation of (xc2x1)-3,4-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane in its optical antipodes is described in U.S. Pat. No. 4,447,622 incorporated herein by reference. Example 1 of U.S. Pat. No.4,447,622 describes the preparation of the minus enantiomer, shown by formula II: 
(In this specification, the compound of formula II is referred to as levormeloxifene.) In example 2 of U.S. Pat. No. 4,447,622, levormeloxifene is obtained as the free base and the hydrochloride salt.
The compounds of formula I may be administered as pharmaceutically acceptable salts. A particularly useful pharmaceutically acceptable salt of levormeloxifene is the hydrogen fumarate salt. This salt form is prepared by dissolving fumaric acid and (xe2x88x92)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane in a common solvent such as e.g. methanol, and crystallizing the resulting salt from the solution.
Tiagabine is disclosed in U.S. Pat. No. 5,010,090 incorporated herein by reference. (2E)-5-amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide is disclosed in WO 97/23508 incorporated herein by reference. Raloxifene is disclosed in U.S. Pat. No. 4,418,068 and U.S. Pat. No. 4,133,814 incorporated herein by reference. Idoxifene is disclosed in EP 260066 B1 and U.S. Pat. No. 4,839,155 incorporated herein by reference. Tamoxifene is disclosed in U.S. Pat. No. 4,536,516 incorporated herein by reference. 4-hydroxy Tamoxifene is disclosed in U.S. Pat. No. 4,623,660 incorporated herein by reference. Toremifene is disclosed in U.S. Pat. No. 4,996,225 incorporated herein by reference. Droloxifene is disclosed in EP 792640 incorporated herein by reference.
An object of the present invention is to provide a novel granulate or oral solid dosage form with improved stability properties.
A further object of the present invention is to provide a novel tablet or capsule with possibility of extension of long term shelf-life.
Further objects of the present invention will become apparent from the specification.
Accordingly, the present invention relates to a wet granulation method for preparing a granulate comprising an active ingredient and one or more carriers, the method comprising
a) formation of a mixture of the active ingredient and one or more carriers,
b) granulation of the mixture and
c) drying the mixture,
wherein the granulation is performed in a high shear mixing means with a temperature regulating means for keeping the temperature below about 40xc2x0 C. in the mixture during granulation.
In another aspect of the present invention the wet granulation method for preparing a granulate comprising an active ingredient and one or more carriers, further comprises processing the granulate into an oral solid dosage formulation. In other words the present invention relates to a wet granulation method for preparing an oral solid dosage formulation comprising an active ingredient and one or more carriers, the method comprising
a) formation of a mixture of the active ingredient and one or more carriers,
b) granulation of the mixture,
c) drying the mixture, and
d) processing the granulate into an oral solid dosage formulation,
wherein the granulation is performed in a high shear mixing means with a temperature regulating means for keeping the temperature below about 40xc2x0 C. in the mixture during granulation. In one embodiment the oral solid dosage formulation is a tablet.. In another embodiment the oral solid dosage formulation is a capsule. In a further embodiment the oral solid dosage formulation, such as tablet or capsule, is coated with a film.
In a further embodiment of the present method the temperature in the granulation mixture is lower than about 35xc2x0 C. In a particular embodiment the temperature is from about 0xc2x0 C. to about 35xc2x0 C., more preferred from about 0xc2x0 C. to about 30xc2x0 C., even more preferred from about 0xc2x0 C. to about 25xc2x0 C., still even more preferred from about 15xc2x0 C. to about 30xc2x0 C., and most preferred from about 20xc2x0 C. to about 25xc2x0 C. In still further embodiments of the present method, which embodiments should be considered independently of each other, the temperature in the granulation mixture is from about xe2x88x9220xc2x0 C. to about 40xc2x0 C., from about xe2x88x9210xc2x0 C. to about 40xc2x0 C., from about xe2x88x9210xc2x0 C. to about 0xc2x0 C., from about 0xc2x0 C. to about 10xc2x0 C., from about 10xc2x0 C. to about 20xc2x0 C., from about 20xc2x0 C. to about 30xc2x0 C., from about 30xc2x0 C. to about 40xc2x0 C., from about 0xc2x0 C. to about 40xc2x0 C., from about 10xc2x0 C. to about 35xc2x0 C., from about 15xc2x0 C. to about 25xc2x0 C., or from about 20xc2x0 C. to about 25xc2x0 C.
In a further embodiment of the present method the active ingredient is selected from non-peptide organic molecules, small peptides and peptide mimetics. In one embodiment the active ingredient is a non-peptide organic molecule. In another embodiment the active ingredient is a small peptide. In a further embodiment the active ingredient is a peptide mimetic. In a further embodiment the active ingredient has a molecular weight of below 1500 daltons, such as from 200 to 1500 daltons, preferably from 500 to 1000 daltons.
In a further embodiment of the present method the active ingredient is selected from non-peptide organic molecules, small peptides and peptide mimetics, such as centchroman, levormeloxifene, tiagabine, (2E)-5-amino-5-methylhex-2-enoic acid N-methyl-N-((1R)-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)-2-(2-naphthyl)ethyl)amide, ipamorelin, raloxifene, idoxifene, tamoxifene and droloxifene or pharmaceutically acceptable salts thereof, each of which is considered to be an alternative embodiment. In a preferred embodiment the active ingredient is levormeloxifene or a pharmaceutically acceptable salt thereof, more preferred levormeloxifene hydrogen fumarate or levormeloxifene hydrogen maleate, most preferred levormeloxifene hydrogen fumarate.
In a still further embodiment of the present method the active ingredient is selected from a compound of formula I 
wherein R is hydrogen or C1-6alkyl; or a pharmaceutically acceptable salt thereof. In one embodiment R is methyl. In another embodiment the compound of formula I is in the trans configuration. In a further embodiment the compound of formula I is 3,4-trans-2,2-dimethyl-3-phenyl-4-[4-(2-pyrrolidin-1-yl)ethoxy)phenyl]-7-methoxychroman (centchroman). In a still further embodiment the compound of formula I is an isolated I-enantiomer. In a further embodiment the compound of formula I is (xe2x88x92)-3R,4R-trans-7-methoxy-2,2-dimethyl-3-phenyl-4-{4-[2-(pyrrolidin-1-yl)ethoxy]phenyl}chromane (levormeloxifene). In a still further embodiment the compound of formula I is in the form of the hydrogen fumarate salt. In a further embodiment the compound of formula I is in the form of the hydrogen maleate salt.
The one or more carriers are such which are commonly used in the pharmaceutical chemistry for preparing granulates, see eg. Remington: The Science and Practice of Pharmacy, 19th Edition (1995) and/or Handbook of pharmaceutical granulation technology, chapter 7, xe2x80x9cDrugs and the pharmaceutical sciencesxe2x80x9d, vol. 81, 1997. In a further embodiment of the present method the one or more carriers are selected from hydrophilic binders, water-soluble diluents, surfactants, detergents, lubricants, disintegrants, antioxidants, non water-soluble diluents and/or other fillers known to the skilled person. In a particular embodiment the one or more carriers comprises at least a hydrophilic binder and a water-soluble diluent.
In a further aspect the present invention relates to a granulate comprising an active ingredient and one or more carriers, obtainable by the wet granulation method for preparing a granulate comprising an active ingredient and one or more carriers, the method comprising
a) formation of a mixture of the active ingredient and one or more carriers,
b) granulation of the mixture and
c) drying the mixture,
wherein the granulation is performed in a high shear mixing means with a temperature regulating means for keeping the temperature below about 40xc2x0 C. in the mixture during granulation. In one embodiment the granulate is obtained by said method.
In a still further aspect the present invention relates to an oral solid dosage formulation comprising an active ingredient and one or more carriers, obtainable by the wet granulation method for preparing an oral solid dosage formulation comprising an active ingredient and one or more carriers, the method comprising
a) formation of a mixture of the active ingredient and one or more carriers,
b) granulation of the mixture,
c) drying the mixture, and
d) processing the granulate into an oral solid dosage formulation,
wherein the granulation is performed in a high shear mixing means with a temperature regulating means for keeping the temperature below about 40xc2x0 C. in the mixture during granulation. In one embodiment the oral solid dosage formulation is obtained by said method. In another embodiment the oral solid dosage formulation is a tablet or capsule, preferably a tablet. In a particular embodiment of the oral solid dosage formulation the preferred range of total mass may be from about 40 mg to about 500 mg depending on the strength of the formulation, more preferred from about 80 mg to about 320 mg, most preferred from about 80 mg to about 120 mg.
In a special aspect of the above methods, if the wet massing step is left out in the disclosed wet granulation method a stable powder (instead of a stable granulation) will be obtained, which powder may be used for administration to a patient, eg. in solution or suspension, or may be compressed into an oral solid dosage form, eg. tablets.
Oral solid dosage formulations or compositions containing an active ingredient, eg. a compound of formula I may be administered one or more times per day or week. An effective amount of such an active ingredient, eg. a compound of formula I is the amount required to effect prophylaxis or treatment of relevant disease-states. Such amount will depend, in part, on the particular disease-state and its severity, and age, weight, and general health of the patient, and other factors evident to those skilled in the art, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge. A typical daily dose will contain a nontoxic dosage range of from about 0.0001 to about 75 mg/kg patient per day of an active ingredient, eg. a compound of formula I, in particular levormeloxifene. A suitable dose of a compound of formula I, such as levormeloxifene, is e.g. from 0.01 to 2.5 mg per day to a patient, eg. a woman.